Methods and compositions for treating inflammatory conditions

Abstract

The present invention is directed to methods of treating an inflammatory condition in a patient. This method includes providing a therapeutic agent that is a vascular endothelial growth factor receptor-3 (VEGFR-3) agonist or a nucleic acid molecule encoding a VEGFR-3 agonist. The present invention is further directed to pharmaceutical compositions and therapeutic systems for treating an inflammatory condition.

What is claimed: 
     
         1 . A method of treating an inflammatory condition in a patient comprising:
 providing a therapeutic agent that is a vascular endothelial growth factor receptor-3 (VEGFR-3) agonist; and   administering the therapeutic agent to the patient having the inflammatory condition, wherein said administering is effective to treat the inflammatory condition.   
     
     
         2 . The method according to  claim 1 , wherein the inflammatory condition is an inflammatory condition occurring in or around a joint. 
     
     
         3 . The method according to  claim 1 , wherein the inflammatory condition is rheumatoid arthritis. 
     
     
         4 . The method according to  claim 1 , wherein the VEGFR-3 agonist is a recombinant VEGF-C protein or active peptide fragment or derivative thereof. 
     
     
         5 . The method according to  claim 4 , wherein the recombinant VEGF-C protein or active peptide fragment or derivative thereof is not a VEGFR-2 agonist. 
     
     
         6 . The method according to  claim 4 , wherein the recombinant VEGF-C protein or active peptide fragment or derivative thereof comprises a cysteine to serine substitution at amino acid position 152 (C152S) or 156 (C156S) of SEQ ID NO:2. 
     
     
         7 . The method according to  claim 1  wherein the VEGFR-3 agonist is administered to the patient in combination with an agent that inhibits VEGF/VEGFR-1 or VEGF/VEGFR-2 signaling. 
     
     
         8 . The method according to  claim 7 , wherein the agent is selected from the group consisting of a VEGFR-1 or VEGFR-2 antibody or aptamer; a VEGFR-1 or VEGFR-2 inhibitory peptide or polypeptide fragment; a polypeptide comprising a soluble VEGFR-1 or VEGFR-2 or fragment thereof; and a VEGF, VEGFR-1, or VEGFR-2 antisense polynucleotide or siRNA. 
     
     
         9 . The method according to  claim 1  wherein the therapeutic agent is administered to the patient in combination with an anti-inflammatory agent selected from the group consisting of a non-steroidal anti-inflammatory drug (NSAID), an analgesic, a glucocorticoid, a disease-modifying anti-rheumatic drug, a dihydrofolate reductase inhibitor, a TNFα inhibitor, a biologic response modifier, and combinations thereof. 
     
     
         10 . The method according to  claim 1 , wherein said administering is carried out orally, subcutaneously, intravenously, intramuscularly, parenterally, intrasynovially, intra-articularly, intraperitoneally, topically, transdermally, or by application to a mucosal surface. 
     
     
         11 . The method according to  claim 2 , wherein said administering is intrasynovially. 
     
     
         12 . A pharmaceutical composition comprising:
 a pharmaceutically acceptable carrier;   a therapeutic agent that is a VEGFR-3 agonist; and   one or more additional therapeutic agents selected from the group consisting of a VEGFR-1 or VEGFR-2 antagonist, an agent that interferes with VEGF/VEGFR-1 or VEGF/VEGFR-2 signaling, an NSAID, an analgesic, a glucocorticoid, a disease-modifying anti-rheumatic drug, a dihydrofolate reductase inhibitor (e.g., methotrexate), a TNFα inhibitor, and a biological response modifier.   
     
     
         13 . The pharmaceutical composition according to  claim 12 , wherein the VEGFR-3 agonist is a recombinant VEGF-C protein or active peptide fragment or derivative thereof. 
     
     
         14 . The pharmaceutical composition according to  claim 13 , wherein the recombinant VEGF-C protein or active peptide fragment or derivative thereof is not a VEGFR-2 agonist. 
     
     
         15 . The pharmaceutical composition according to  claim 13 , wherein the recombinant VEGF-C protein or active peptide fragment or derivative thereof comprises a cysteine to serine substitution at amino acid position 152 (C152S) or 156 (C156S) of SEQ ID NO:2. 
     
     
       
         10 
       
     
     
         16 . A therapeutic system for treating an anti-inflammatory condition comprising:
 a first pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutic agent that is a VEGFR-3 agonist; and   a second pharmaceutical composition comprising a pharmaceutically acceptable carrier and one or more additional therapeutic agents selected from the group consisting of a VEGFR-1 or 2 antagonist, an agent that interferes with VEGF/VEGFR-1 or 2 interaction, an NSAID, an analgesic, a glucocorticoid, a disease-modifying anti-rheumatic drug, a dihydrofolate reductase inhibitor (e.g., methotrexate), a TNFα inhibitor, and a biological response modifier.   
     
     
         17 . The therapeutic system according to  claim 16 , wherein the VEGFR-3 agonist is a recombinant VEGF-C protein or active peptide fragment or derivative thereof. 
     
     
         18 . The therapeutic system according to  claim 17 , wherein the recombinant VEGF-C protein or active peptide fragment or derivative thereof is not a VEGFR-2 agonist. 
     
     
         19 . The therapeutic system according to  claim 17 , wherein the recombinant VEGF-C protein or active peptide fragment or derivative thereof comprises a cysteine to serine substitution at amino acid position 152 (C152S) or 156 (C156S) of SEQ ID NO:2.